Anti-misuse microparticulate oral pharmaceutical form

Abstract

The present invention relates to solid microparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse of the pharmaceutical active principle they contain. The invention relates to a solid oral pharmaceutical form which is characterized in that it contains anti-misuse means, in that at least part of the active principle it comprises is contained in coated microparticles for modified release of the active principle, and in that the coated microparticles have a coating layer which assures modified release of the active principle and simultaneously imparts crushing resistance to the coated microparticles so as to avoid misuse.

The invention claimed is: 
     
       1. An anti-misuse solid oral pharmaceutical formulation, whereby said formulation comprises coated microparticles resistant to crushing for the modified release of at least one active principle (AP) selected from the group consisting of: amphetamines, narcotics, anorexigenics, antidepressants, antiepileptics, antiparkinsonism substances, anxiolytics, barbiturates, benzodiazepines, hypnotics, neuroleptics, opioids, psychostimulants, psychotropic substances and mixtures thereof,
 wherein said coated microparticles are inert cores covered with at least one layer containing AP and at least one coating layer (Ra), 
 whereby said at least one coating layer (Ra) represents a fraction by weight (Tp) greater than 30%, expressed in % by dry weight, based on the total weight of the coated microparticles, 
 whereby said at least one coating layer (Ra) comprises:
 at least one film-forming (co)polymer (A1) insoluble in the gastrointestinal juices present in a proportion of 60% to 90% by weight on a dry basis, relative to the total mass of the coating composition; 
 at least one (co)polymer soluble in the gastrointestinal juices (A2) present in a proportion of 5% to 40% by weight on a dry basis, relative to the total mass of the coating composition; 
 at least one plasticizer (A3) present in a proportion of 1% to 30% by weight on a dry basis, relative to the total mass of the coating composition; and 
 wherein said formulation further comprises at least one viscosifier (Vb). 
 
 
     
     
       2. The pharmaceutical formulation of  claim 1 , whereby said formulation further comprises at least one sequestering agent (Q) capable of forming a complex with the AP in solution. 
     
     
       3. The pharmaceutical formulation of  claim 1 , whereby, in the event of crushing, said at least one coating layer (Ra) allows maintenance of a modified release of the AP for at least some of said coated microparticles. 
     
     
       4. The pharmaceutical formulation of  claim 3 , whereby, in the event of crushing, said at least one coating layer (Ra) allows maintenance of a modified release of the AP for at least 40% of said coated microparticles. 
     
     
       5. The pharmaceutical formulation of  claim 1 , whereby said at least one coating layer (Ra) further comprises at least one surfactant, lubricant, mineral or organic filler (A4) in the following amount (in % by weight, based on the total weight of the coating):
   0 ≦A 4≦40.
 
 
     
     
       6. The pharmaceutical formulation of  claim 5 , whereby said at least one film-forming (co)polymer (A1) is selected from the group consisting of: water-insoluble cellulose derivatives, ethyl cellulose, cellulose acetate, acrylic polymers, copolymers of (meth)acrylic acid alkyl ester, copolymers of acrylic and methacrylic acid esters carrying at least one quaternary ammonium group, copolymers of alkyl (meth)acrylate and trimethylammonioethyl methacrylate chloride), polyvinyl acetates, and mixtures thereof;
 whereby said at least one (co)polymer soluble in the gastrointestinal juices (A2) is selected from the group consisting of: nitrogen-containing (co)polymers, polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP), poly-N-vinyllactams, water-soluble cellulose derivatives, polyvinyl alcohols (PVA), polyalkylene oxides, polyethylene oxides (PEO), polyethylene glycols (PEG), and mixtures thereof; 
 whereby said at least one plasticizer (A3) is selected from the group consisting of: cetyl alcohol esters, glycerol, glycerol esters, acetylated glycerides, glycerol monostearate, glyceryl triacetate, glycerol tributyrate, phthalates, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, sebacates, diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, vegetable oils, fumarates, diethyl fumarate, malates, diethyl malate, oxalates, diethyl oxalate, succinates, dibutyl succinate, butyrates, cetyl alcohol esters, salicylic acid, triacetin, malonates, diethyl malonate, castor oil, and mixtures thereof; 
 and whereby said at least one surfactant, lubricant, mineral or organic filler (A4) is selected from the group consisting of: anionic surfactants, alkali metal, alkaline earth metal salts of fatty acids, stearic acid, oleic acid, non-ionic surfactants, polyethoxylated oils, polyethoxylated hydrogenated castor oil, polyoxyethylene/polyoxypropylene copolymers, polyethoxylated sorbitan esters, polyethoxylated castor oil-based compounds stearates, calcium stearate, magnesium stearate, aluminum stearate, zinc stearates, stearylfumarates, sodium stearylfumarate, glycerol behenates, talcum, colloidal silica, titanium oxide, magnesium oxide, bentonite, microcrystalline cellulose, kaolin, aluminum silicate, and mixtures thereof. 
 
     
     
       7. The pharmaceutical formulation of  claim 1 , whereby said coated microparticles have a mean diameter less than or equal to 1000 μm. 
     
     
       8. The pharmaceutical formulation of  claim 1 , whereby said at least one viscosifier (Vb) is selected from viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, such that said viscosifier (Vb) is capable of increasing the viscosity of the extraction liquid so as to inhibit misuse, especially by injection. 
     
     
       9. The pharmaceutical formulation of  claim 8 , whereby said at least one viscosifier (Vb) is selected from the group consisting of: polyacrylic acids, polyacrylic acids derivatives, polyalkylene glycols, polyethylene glycol, polyalkylene oxides, polyethylene oxides, polyvinylpyrrolidones, gelatins, polysaccharides, sodium alginate, pectins, guars, xanthans, carrageenans, gellans, cellulose derivatives, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and mixtures thereof. 
     
     
       10. The pharmaceutical formulation of  claim 8 , whereby said at least one viscosifier (Vb) is a polyoxyethylene with an average molecular weight of 1 million g/mol to 8 million g/mol. 
     
     
       11. The pharmaceutical formulation of  claim 8 , whereby said at least one viscosifier (Vb) is capable of increasing the extraction viscosity to a value greater than or equal to 100 mPa·s in an extraction volume of 2.5 ml so as to trap the extracted AP in the viscous medium. 
     
     
       12. The pharmaceutical formulation of  claim 8 , whereby said part of said at least one viscosifier (Vb) is in the form of microparticles that are inseparable from the coated or uncoated microparticles of AP. 
     
     
       13. The pharmaceutical formulation of  claim 2 , whereby said at least one sequestering agent (Q) comprises a salt containing at least one ion capable of forming a complex with the extracted AP salt in solution. 
     
     
       14. The pharmaceutical formulation of  claim 13 , whereby said at least one ion is an organic ion with opposite polarity to that of the AP in solution, such that said at least one ion forms a complex with the extracted AP salt in solution. 
     
     
       15. The pharmaceutical formulation of  claim 14 , whereby said at least one sequestering agent (Q) is present in a first phase separate from at least one second phase, whereby said at least one second phase comprises at least one AP salt. 
     
     
       16. The pharmaceutical formulation of  13 , whereby said formulation comprises microparticles of AP salt and microparticles of sequestering agent (Q). 
     
     
       17. The pharmaceutical formulation of  claim 16 , whereby said microparticles have a size distribution and density thereby inhibiting separation by sieving. 
     
     
       18. The pharmaceutical formulation of  claim 14 , whereby said at least one ion is an organic anion, organic metal cation, or mixture thereof. 
     
     
       19. The pharmaceutical formulation of  claim 13 , whereby said at least one sequestering agent (Q) comprises a salt selected from the group consisting of:
 anionic organic salts, anionic polymers, carboxymethyl cellulose, carboxymethyl cellulose derivatives, crosslinked carboxymethyl cellulose, crosslinked carboxymethyl cellulose derivatives, polysaccharides, phosphates, saponified fatty acids, self-emulsifying glyceryl monooleates, polyamino acids, proteins, peptides, 
 cationic metallic salts, cationic organic salts, cationic polymers, and mixtures thereof. 
 
     
     
       20. The pharmaceutical formulation of  claim 13 , whereby said at least one sequestering agent (Q) is a salt that is either a strongly acidic cation exchange resin when the AP is cationic, or a strongly basic anion exchange resin when the AP is anionic. 
     
     
       21. The pharmaceutical formulation of  claim 20 , wherein said at least one sequestering agent (Q) is a derivative of a styrene/divinylbenzene copolymer. 
     
     
       22. The pharmaceutical formulation of  claim 20 , wherein said at least one sequestering agent (Q) is a derivative of a sulfonated styrene/divinylbenzene copolymer. 
     
     
       23. The pharmaceutical formulation of  claim 20 , wherein said at least one sequestering agent (Q) is a styrene/divinylbenzene copolymer carrying quaternary ammonium groups. 
     
     
       24. The pharmaceutical formulation of  claim 20 , wherein said at least one sequestering agent (Q) is a crosslinked methacrylic acid/divinylbenzene copolymer or one of its salts. 
     
     
       25. The pharmaceutical formulation of  claim 20 , wherein said exchange resin is a phenolic polyamine. 
     
     
       26. The pharmaceutical formulation of  claim 13 , whereby the ionic charge of said at least one sequestering agent (Q) can complex at least part of the AP contained in the unit form. 
     
     
       27. The pharmaceutical formulation of  claim 13 , whereby said at least one sequestering agent (Q) is in the form of microparticles that are inseparable from the coated or uncoated microparticles of AP. 
     
     
       28. The pharmaceutical formulation of  claim 13 , whereby said formulation further comprises microparticles of at least one viscosifier (Vb), and whereby said microparticles of at least one sequestering agent Q and microparticles of at least one viscosifier (Vb) are distinct from said microparticles of AP. 
     
     
       29. The pharmaceutical formulation of  claim 13 , whereby said microparticles of AP, said microparticles of at least one viscosifier (Vb) and said microparticles of at least one sequestering agent Q have a similar size distribution and density, thereby inhibiting separation from one another by sieving. 
     
     
       30. The pharmaceutical formulation of  claim 1 , whereby said formulation further comprises at least one excipient in a free state which contributes to the crushing resistance of said coated microparticles of AP. 
     
     
       31. The pharmaceutical formulation of  claim 30 , whereby said at least one excipient is selected from the group consisting of: calcium stearate, glycerol palmitostearate, magnesium oxide, polyalkylene glycols, polyethylene glycols, polyvinyl alcohol, sodium benzoate, stearic acid, maize starch, talcum, colloidal silica, zinc stearate, magnesium stearate, stearylfumarate, and mixtures thereof. 
     
     
       32. The pharmaceutical formulation of  claim 1 , whereby said formulation is such that it cannot be converted to a dry form with immediate release of the AP to permit abuse by sniffing. 
     
     
       33. The pharmaceutical formulation of  claim 1 , whereby said formulation is such that it cannot be converted to an injectable form with immediate release of the AP. 
     
     
       34. The pharmaceutical formulation of  claim 1 , whereby said formulation further comprises at least one immediate release AP. 
     
     
       35. The pharmaceutical formulation of  claim 1 , whereby said at least one AP is selected from the group consisting of: anileridine, acetorphine, acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alpha-cetylmethadol, alpha-meprodine, alpha-prodine, alpha-methadol, alpha-methylfentanyl, alpha-methylthiofentanyl, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, beta-meprodine, beta-methadol, beta-prodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethylthiambutene, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morpheridine, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, pholcodine, piminodine, piritramide, proheptazine, propanolol, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thebacon, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof. 
     
     
       36. The pharmaceutical formulation of  claim 1 , whereby said at least one AP is selected from the group consisting of: oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride, tramadol hydrochloride, and mixtures thereof. 
     
     
       37. The pharmaceutical formulation of  claim 1 , whereby said formulation does not contain an AP antagonist. 
     
     
       38. The pharmaceutical formulation of  claim 1 , whereby said formulation comprises at least two different populations of coated microparticles of AP, whereby each population of coated microparticles has different release kinetics. 
     
     
       39. The pharmaceutical formulation of  claim 13 , whereby said at least one sequestering agent (Q) comprises a salt selected from the group consisting of:
 sodium dodecylsulfate, sodium docusate, methyl methacrylate methacrylic acid copolymer, crosslinked polyacrylic acids, (sulfonate)propylene glycol alginate, glucuronates, citrates, acetates, carbonates, gluconates, succinates, glycerophosphates, lactates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames, acetic acid salts, succinic acid salts, citric acid salts, stearic acid salts, palmitic acid salts, alginate, chitosan, xanthan gum, gum arabic, 
 quaternary ammonium salts, trimethyltetradecylammonium bromide, benzethonium chloride, polyamino acids, proteins, Ca salts, Fe salts, Mg salts, Zn salts, copolymers of acrylic and methacrylic acid esters with a low content in quaternary ammonium groups, copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters, and mixtures thereof. 
 
     
     
       40. The pharmaceutical formulation of  claim 13 , whereby said at least one sequestering agent (Q) comprises albumins, caseins, globulins, enzymes, and mixtures thereof. 
     
     
       41. The pharmaceutical formulation of  claim 1 , whereby said coated microparticles have a mean diameter comprised between 100 and 600 μm. 
     
     
       42. The pharmaceutical formulation of  claim 1 , whereby said coated microparticles have a mean diameter comprised between 100 and 300 μm. 
     
     
       43. A method of treating pain, whereby said method comprises use of the pharmaceutical formulation of  claim 1 . 
     
     
       44. A method of combating the misuse of AP, whereby said method comprises use of the pharmaceutical formulation of  claim 1 .